DESCRIPTION (Applicant's Abstract): In the mammalian CNS, gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter. The most powerful influence of the cerebellar cortex on the deep cerebellar nuclear (DCN) neurons is to exert an inhibition through the GABA-ergic Purkinje cells. The main influence of the cerebellar cortex on motor coordination is, therefore, through inhibitory postsynaptic currents (IPSCs) in DCN cells. Results from this laboratory indicate that GABA-A receptor-mediated IPSCs in DCN neurons undergo long-term depression (LTD) following a high frequency activation of the inputs. The LTD can be induced heterosynaptically and by increases in postsynaptic [Ca2]. During LTD, DCN neuronal response to applied THIP, a GABA-A agonist, is decreased, suggesting a postsynaptic alteration. Since reductions in the influence of the cerebellar cortex on DCN neurons should have profound implications for cerebellar control of motor coordination, studies are proposed to examine the mechanisms involved in the LTD. In the hippocampus, GABA-ergic IPSCs can regulate epileptic activity and affect the long-term potentiation (LTP) of the excitatory transmission, implicated as a mechanism for learning and memory. LTP of hippocampal IPSCs occurs following a high frequency activation of afferent fibers. The LTP appears to be due to a potentiation at the GABA-ergic synapses on Ca1 neurons, is not dependent of LTP appears to be due to a potentiation at the GABA-ergic synapses on CA1 neurons, is not dependent on changes at gluatmatergic synapses and is greater if the postsynaptic Ca2+ is chelated or protein kinases C (PKC) inhibited, suggesting that postsynaptic Ca2+ and PKC ard involved in controlling, rather than inducing, LTP of IPSCs. Mechanisms involved in the tetanus-induced LTP of the IPSC, are unclear. Activations of presynaptic PKC and protein kinase A (PKA) are implicated in increasing the quantal release of GABA and an increase in evoked IPSCs. Studies are proposed in this application to determine if presynaptic PKC or PKA are involved in the tetanus-induced LTP of the IPSCs. Recordings of miniature and evoked IPSCs from DCN and CA1 neurons in slice preparations will be made with the whole cell patch clamp technique. The specific aims are: to examine (1a) whether glutamatergic inputs to DCN neurons contribute to LTD of the IPSC; (1b) if Ca2+ -influxes through the NMDA receptor-gated channels or through the voltage-gated L-channels contribute to LTD; (1c) whether postsynaptic protein phosphateses participate in the LTD; and (1d) if the depression is associated with a change in GABA release of if active GABA synapses become silent during LTD; (2a) whether the tetanus-induced LTP or GABA-A receptor-mediated IPSCs in hippocampal CA1 neurons is due to an increase in transmitter release; and if so, (2b) if presynaptic PKC and PKA are involved in the LTP.